Expression of an interleukin-2 partial agonist enhances regulatory T cell persistence and efficacy in mouse autoimmune models

  • Nat Commun. 2025 May 27;16(1):4891. doi: 10.1038/s41467-025-60082-z.
Janie Robert  1 ,  Manon Feuillolay  1  2 ,  María de Temple-Llavero  1 ,  Reginald Florian Akossi  1 ,  Vanessa Mhanna  1  2 ,  Mustapha Cheraï  2 ,  Gwladys Fourcade  1 ,  Frédéric Charlotte  3 ,  Nicolas Tchitchek  1 ,  Tian Mi  4 ,  Benjamin Youngblood  4 ,  Thomas Vazquez  5 ,  Michelle Rosenzwajg  1  2 ,  David Klatzmann  6  7
Affiliations
  • 1. Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3), F-75005, Paris, France.
  • 2. Assistance Publique - Hôpitaux de Paris, Clinical Investigation Center for Biotherapy and Immunology (CIC-BTi), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
  • 3. Assistance Publique - Hôpitaux de Paris, Pathology department, Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
  • 4. Immunology, MS 351, St. Jude Children's Research Hospital, Memphis, USA.
  • 5. ILTOO Pharma, 10 rue des Reculettes, 75013, Paris, France.
  • 6. Sorbonne Université, INSERM, UMRS959, Immunology-Immunopathology-Immunotherapy (i3), F-75005, Paris, France. [email protected].
  • 7. Assistance Publique - Hôpitaux de Paris, Clinical Investigation Center for Biotherapy and Immunology (CIC-BTi), Hôpital Pitié-Salpêtrière, F-75013, Paris, France. [email protected].
PMID: 40425532 DOI: 10.1038/s41467-025-60082-z
Abstract

Regulatory T (Treg)-based cell therapy holds promise for autoimmune and inflammatory diseases, yet challenges remain regarding the functional stability and persistence of transferred Tregs. Here we engineer Tregs to express a partial agonist form of IL-2 (IL-2pa) to enhance persistence while avoiding toxicity from excessive signaling. Mouse Tregs expressing wild-type IL-2 (Tregs-IL2wt) have only a transient growth advantage, limited by toxicity from likely excessive signaling. By contrast, mouse Tregs-IL2pa exhibit sustained expansion, long-term survival in immunocompetent mice for over a year, and bystander expansion of endogenous Tregs. Tregs-IL2pa maintain a stable activated phenotype, Treg-specific demethylation, and a diverse TCR repertoire. In vivo, prophylactic transfer of Tregs-IL2pa ameliorates multi-organ autoimmunity in a Treg depletion-induced mouse autoimmune model. Lastly, compared with control Treg, human Tregs-IL2pa show enhanced survival in the IL-2-depleted environment of immune-deficient mice and improved control of xenogeneic graft-versus-host disease. Our results thus show that IL-2pa self-sufficiency enhances the stability, durability and efficacy of Treg therapies in preclinical settings.

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